Paclitaxel binding to L-PGDS: Improved solubility through hydrophobic bonds and CRGDK targeting peptides.
Recent advances in drug discovery research have led to the development of numerous drug candidate compounds with high therapeutic efficacy. However, many of these compounds possess properties that make them difficult to handle, such as poor water solubility and large molecular weights. This leads to poor absorption in the body and difficulty in achieving sufficient therapeutic effects. Further, the drugs distribute to normal tissues, which lead to severe side effects. Fortunately, active research is underway to develop drug delivery systems (DDS) that effectively solubilize these compounds and efficiently deliver them to cancerous tissues.
A research group led by Professor Takashi Inui from Osaka Metropolitan University’s Graduate School of Agriculture attempted to develop a DDS that specifically transports Paclitaxel (PTX), an anticancer drug with poor water solubility and the molecular weight of 854, to cancerous tissue. The researchers utilized the lipocalin-type prostaglandin D synthase (L-PGDS) enzyme as a novel DDS carrier to efficiently transport PTX.
Docking simulations and solubility testing revealed that PTX primarily binds via hydrophobic interactions to the upper region of the L-PGDS β-barrel protein structure. In turn, its solubility improved approximately 3,600-fold compared to when it's suspended in phosphate-buffered saline. Further, the team attached the targeting peptide CRGDK, which binds to the neuropilin-1 receptor expressed on cancer cell surfaces, to the C-terminus of L-PGDS and created L-PGDS-CRGDK for selective delivery to cancer tissues.
When using a mouse model implanted with MDA-MB-231 breast cancer cells to evaluate drug effectiveness, the commercially available formulation demonstrated antitumor effects during the administration period, but the effects weakened after administration ceased. In contrast, PTX/L-PGDS and PTX/L-PGDS-CRGDK maintained antitumor effects even after administration ceased, with PTX/L-PGDS-CRGDK exhibiting the highest tumor suppression effect.
“This study demonstrated that L-PGDS can bind relatively large drugs with molecular weights up to approximately 850 and further revealed that introducing a targeting peptide enables the selective delivery of anticancer drugs to cancer cells. The DDS developed in this study is anticipated to significantly contribute to the advancement of future cancer treatments as a novel delivery strategy for poorly soluble anticancer drugs,” stated Professor Inui.
The findings were published in ACS omega.
Conflict of Interest
The authors declare no competing financial interest.
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